Optimized antigen-binding constructs of A33, an antibody that binds to colon cancer, have been engineeredto be non-immunogenic; retain antigen-binding ability, and clear faster from non-tumor sites. Currentimmunoglobulin-based therapy of colon cancer as well as other solid tumors is limited by low tumornontumorratios. We have undertaken an effort to increase this ratio by a) increasing serum clearance; b)increasing tumor penetrance of antigen-binding construct, and c) developing bispecific antigen-bindingconstructs that recognize tumor antigen and chelates that can carry radionuclides.This grant aims to study two antigen-binding constructs: a single chain Fv (sFv) fragment, and a fusionprotein consisting of sFv A33 and a sFv against a chelate (DOTA). The clinical trials will be carried out inpatients with measurable disease: the initial trials in patients scheduled to undergo biopsy of their disease,followed by trials using positron-emitting radiometals and serial PET imaging. These studies will helpdetermine the optimum antigen-binding construct for subsequent radioimmunotherapy.
Specific Aim 1 will determine the tumor targeting abilities and optimum route of administration of sFv A33 inpatients with measurable metastatic colon cancer. The first study will be with IV 111ln-DOTA-sFv A33 in presurgicalpatients with metastatic colon cancer; if this study demonstrates targeting to normal colon and/ortumor, we will carry out a comparable study with intra-arterial 111ln-DOTA-sFv A33, to determine whetherroute of administration influences targeting. These will be followed by a PET study with 86Y-DOTA-sFv A33.We are in the process of producing a bispecific antigen-binding construct consisting of 2 sFv molecules:one sFv targets the A33 antigen while the other sFv reacts with metal-conjugated DOTA chelate.
Specific Aim 2 will determine the optimal route of administration and targeting of this construct, with clinicaltrial design being similar to that in Specific Aim 1.
Specific Aim 3 will evaluate tumor targeting using PET, and immunogenicity of a novel humanized A33 IgG.These studies will form the template for studies to determine the utility of sFv A33 in the detection andtreatment of colon cancer; the utility of bispecific constructs in the detection and treatment of colon cancer;and the ability of a novel non-immunogenic A33 IgG to specifically target colon cancer.
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